16alpha,17alpha-ethylene and substituted ethylene pregnane derivatives and process



United States Patent Oflice 3,431,256 Patented Mar. 4, 1969 ABSTRACT OFTHE DISCLOSURE New 16a,17a-ethylene and 160:,17a-S11b5titt1t6d ethylenederivatives of the pregnane series prepared by photochemical addition ofan olefin or substituted olefin to a A -one of the pregnane seriesuseful as progestational agents.

This invention relates to novel cyclopentanophenanthrene derivatives andto a process for the production thereof. More specifically thisinvention relates to novel 16a,l7a-ethylene and 16a,17a-substitutedethylene derivatives of the pregnane series.

The compounds of the present invention may be repre sented by thefollowing formula:

wherein Z is a carbon-carbon single bond, a carbon-car bon double bondor the group "oXY bridging the C-1 and C2 carbon atoms, each of X and Ybeing hydrogen, chloro or fluoro;

Z is a carbon-carbon single bond, a carbon-carbon double bond or thegroup bridging the C-6 and C-7 carbon atoms, each of X and Y beinghydrogen, chloro or fluoro;

R is hydrogen, chloro or fluoro;

R is hydrogen, chloro, fluoro, methyl or trifluoromethyl, R being in thej3-eonfiguration When Z is the group ICXY and R being in either the aor,B-configuration when Z is a carbon-carbon single bond;

R is hydrogen or methyl, R being methyl when Z is the carbon-carbondouble bond;

R is an oxygen atom or the group in which R is hydrogen,tetrahydropyranyl or a hydrocarbon carboxylic acyl group of less than 12carbon atoms, R being an oxygen atom when Z is a double bond; Each of Aand B is hydrogen, chloro, fluoro or an alkyl group of from 1 to 4carbon atoms;

Each of D and E is hydrogen, chloro, fluoro, phenyl,

an alkyl group of from 1 to 4 carbon atoms, an alkoxy group of from 1 to4 carbon atoms; or a haloalkyl group of from 1 to 4 carbon atoms; and

A and B or D and E taken together are methylene or difluoromethylene.

The compounds of the present invention demonstrate hormonal propertiescharacteristic of progestational agents and are useful in fertilitycontrol and the management of various menstrual disorders. The compoundsalso possess hormonal properties characteristic of anti-androgenic,anti-gonadotrophic and anti-estrogenic agents. These compounds may beadministered via usual routes in the standard pharmaceuticalcompositions and at dosages appropriate for the particular conditionbeing treated.

The compounds of the present invention are prepared from intermediatesof the following formula:

i=0 l R I II Ac0 1 1, (III) wherein each of A, B, D and E is aspreviously defined, While irradiating with ultraviolet light of aWavelength in the range of about 270 to 330 m in the presence of aninert organic solvent such as benzene, dioxane and the like, preferablybenzene. Under these conditions the olefin adds across the A -doublebond with the orientation of the resulting substituted ethylene groupwith respect to the carbon atoms at 16, 17 positions being predominantlya.

While the time for this reaction will in part be dependent upon thereactivity of the reagents, a reaction time of a few hours, e.g., 4 to 5hours is generally adequate for ethylene and for substituted olefinswhose substituents contribute a positive inductive effect to the doublebond, such as alkyl. Longer periods for the reaction time e.g. up to 40or 50 hours may be required for those olefins whose substituentscontribute a negative inductive effect to the double bond, such asfluoro or chloro. In any event, the progress of the reaction may bereadily followed by observing the U.V. spectra of the reaction mixture.This reaction may be represented as follows:

G Ha

Further elaboration of the product of the principal reaction may berepresented by the following general reaction scheme. A 21-chloro orfiuoro substituent is introduced, preferably at this stage, butalternatively at a later stage, by treatment with bromine to give a 21-bromo intermediate, and treatment of the intermediate with a molarequivalent of lithium chloride in dimethylformamide or a molarequivalent of silver fluoride in acetonitrile to afford the 2l-chloro or21-fiuoro compounds of the present invention, respectively.

In those instances in which Z is a methylene or dihalomethylenesubstituent bridging the lulu-positions, the compounds of Formula IV,wherein Z is a carbon-carbon single bond and the configuration of thehydrogen atom in the -position is a, are hydrolyzed as with potassiumbicarbonate in methanol to yield the corresponding 3-hydroxy derivative,which is converted to the corresponding 3-keto compound throughtreatment with chromic trioxide in pyridine. Bromination of this ketocompound as with bromine in acetic acid, followed by dehydrobrominationof the resulting 2-bromo intermediate as with calcium carbonate, nextyields the 16a,I7a-ethYlCl'l6-5oc-PI6gIl-1- ene-3,20-dione. This Acompound is then allowed to react with an alkali or alkaline earth metalsalt of an acid having a formula WCXYCOOH in which W is chloro or iodoand each of X and Y is hydrogen, fiuoro or chloro, at least one of X andY being other than hydrogen. When a lotion-methylene substituent isdesired, this group is introduced through the action ofdimethylsulfoxonium methylide in dimethylsulfoxide, preferably afterreducing the keto groups in the 3- and 20-position with sodiumborohydride and back-oxidizing the 3-hydroxy group with manganesedioxide or 2,3-dichloro-5,6-dicyanobenzoquinone. The 20-keto group maybe regenerated after introduction of the lulu-methylene group by simpleoxidation with chromic trioxide in pyridine. Bromination of theresultant :,20t-II16thY16116-3-kfit0 compound and dehydrobromination asdescribed above yields the corresponding 3-keto-A derivative.

The compounds of Formula IV wherein Z is a double bond may be convertedto the 3-keto-A derivatives directly through hydrolysis as describedabove to yield the S-hydroxy derivative, followed by oxidation underconventional Oppenauer conditions.

With the exception of a methyl group, a o-substituent is next introducedthrough formation of the enol ether as by the action of ethylorthoformate and an acid catalyst such as p-toluenesulfonic acid.Fluorination of the intermediate with perchloryl fluoride, followed byacid isomerization, affords the 3-keto-6a-fluoro-A -ene compounds whiletreatment of the enol ether intermediate with N-chlorosuccinimide,followed by acid isomerization, affords the 6a-chloro compounds.Irradiation of the intermediate in iodotrifiuoromethane affords the6oc-trifiuoromethyl compounds. A 6-methyl substituent is introduced byfirst protecting the -keto group of a compound of Formula IV wherein Zis a double bond through formation of a ketal, treating the New withmonoperphthalic acid in chloroform to give a 5a,6aoxido intermediate andallowing the thus-formed intermediate to react with a methyl Grignardreagent. The thus-formed 3-keto-5a-hydroxy-6,8-methyl compound isreadily converted to the 3-keto-6u-methyl-A -ene compounds throughtreatment with sodium hydroxide.

Introduction of the 4,6-diene system may next be accomplished either bythe action of chloranil in t-butanol or xylene, or through initialformation of the enol ether as previously described, followed bytreatment of this enol ether with2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Treatment of 3-keto-A -diene with sodium chlorodifluoroacetate or withdimethylsulfoxonium methylide in the manner previously described yieldsthe corresponding deriva ive having a difiuoromethylene or methylenegroup respectively bridging the 6a,7q-Garbon atoms,

Introduction of the 3-keto-A -diene system is effected in a conventionalmanner, as for example by the action of2,3-dichloro-5,6-dicyanobenzoquinone, while conversion of a 3-keto-A-diene to the corresponding 3-keto-l, 4,6-triene may be accomplished viathe action of chloranil. The 3-tetrahydropyranyl or 3-acyloxy group isintroduced by reduction of 3-keto-A -ene with an alkali metal hydridesuch as sodium borohydride in an inert solvent such as tetrahydrofuranto afford a 3-hydroxy group and treatment of the 3-hydroxy group withdihydropyran and p-toluenesulfonic acid in an inert solvent to yield thecorresponding 3-tetrahydropyranyloxy compounds of the present invention.In a similarly conventional manner, treatment of the 3-hydroxy compoundwith a molar equivalent of a hydrocarbon carboxylic acid chloride or ahydrocarbon carboxylic acid anhydride in pyridine gives the 3-acyloxycompounds. The hydrocarbon carboxylic acyl group of the presentinvention will contain less than 12 carbon atoms and may be of astraight, branched, cyclic or cyclic-aliphatic chain structure. Thisstructure may be saturated, unsaturated or aromatic and optionallysubstituted by groups such as hydroxy, alkoxy containing up to 5 carbonatoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno,and the like. Typical esters thus include acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, amino acetate, B-chloropropionate, adamantoateand the like.

The following examples will describe the present invention with specificembodiments and applications; other modifications thereof will bereadily apparent to those skilled in the art without department from thespirit and scope of the invention as defined in the appended claims. Inthe naming of the 16a,17u-ethylene derivatives it is understood that inconnection with the substituents D and E, the carbon atoms attached tothe (3-16 carbon atom of the steroid nucleus is designated as 1', and inconnection with the substituents A and B, the carbon atom attached tothe C-17 carbon atoms of the steroid nucleus is designated at 2'.

EXAMPLE 1 A mixture of l g. of 3,8,l7ot-dihydroxy-Sa-pregnan-ZO- one, 4ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand atroom temperature for 15 hours. The mixture is then poured into ice waterand the solid which forms is collected by filtration, washed with waterand dried to yield 3fl-acetoxy-17a-l1ydroxy-5u-pregnan-20-one which maybe further purified through recrystallization from acetonezhexane.

To a suspension of 1 g. of 3,8-acetoxy-17ot-hydroxy-5apregnan-ZO-one in27 ml. of methanol and 1 ml. of water, under nitrogen, is added 1.4 g.of semicarbazide hydrochloride and 0.74 g. of sodium bicarbonate. Themixture is heated at reflux for three hours and then at 45 C. for 20hours. The suspension is cooled and 36 ml. of water are slowly added toit. The solid is collected by filtration, washed with water and dried toyield 3B-acetoxy-17uhydroxy-5a-pregnan-20-semicarbazone which isrecrystallized from pyridinezmethanol.

A solution of 1 g. of3B-acetoxy-17a-hydroxy-5ot-pregnan-ZO-semicarbazone in 20 ml. of aceticacid and 1 ml. of acetic anhydride is heated at reflux under nitrogenfor 1 hour. The reaction mixture is then concentrated under reducedpressure to a volume of about 12 ml. and treated with 6 m1. of water and3 ml. of pyruvic acid. The mixture is allowed to stand at roomtemperature for 40 hours and at 60 C. for 2 hours and is then dilutedwith water and extracted with chloroform. These extracts are washed withwater, dried over magnesium sulfate and evaporated to dryness underreduced pressure. The residue is chromatographed on neutral alumina withbenzene to yield 3B-acet0xy-5wpregn-16-en-20-one which may berecrystallized from acetonezether.

A mixture of 2.0 g. of 3/i-acetoxy-5a-pregn-l6-en-20- one in ml. ofbenzene is irradiated with a 70 Watt Hanan high pressure mercury vaporlamp with a Pyrex filter at room temperature while bubbling ethylenethrough the solution. At the end of the reaction time which may bedetermined by U.V. spectroscopy, the reaction mixture is evaporated todryness, chromatographed on silica and the product eluted with ethylacetate-benzene to yield 3fi-acetoxy-16a,17a-ethylene-Sa-pregnan-ZO-Onewhich is recrystallized from methanohmethylene chloride.

One gram of 3B-acetoxy-16a,17a-ethylene-5u-pregnan- 20-one is allowed tostand at room temperature for 15 hours with 1 g. of potassiumbicarbonate in 10 ml. of water and 90 ml. of methanol. At the end ofthis time, the methanol is evaporated under reduced pressure and theresidue is extracted with ethyl acetate and water. Evaporation of theethyl acetate from these extracts yields 33-hydroxy-l6a,17a-ethylene-5a-pregnan-ZO-Qne which is collected byfiltration and recrystallized from acetone: hexane.

To a stirred solution of 1 g. of3fi-hydroxy-16a,17aethyIene-Sa-pregnan-ZO-one in 10 ml. of acetone,cooled to C., is added under nitrogen a solution of 8 N chromic acid(prepared by mixing 26 g. of chromium trioxide with 23 ml. ofconcentrated sulfuric acid and diluting with water to 100 ml.) until thecolor of the reagent persists in the mixture. The mixture is thenstirred for minutes at 0-5" C. and diluted with water. The solid whichforms is collected by filtration, washed with water and dried undervacuum to yield 16a,l7ot-ethylene 5a-pregnan-3,20-dione which may befurther purified by recrystallization from acetonezhexane.

To a stirred solution of 1 g. of 16a,17a-ethylene-5otpregnan-3,20-dioneand 6.6 g. of p-toluenesulfonic acid in 300 ml. of glacial acetic acidis added, over a minute period, a solution of 1.1 molar equivalent ofbromine and 2.45 g. of sodium acetate in 110 ml. of glacial acetic acid.After stirring for an additional 10 minute period, a solution of 75 g.of sodium acetate in 150 ml. of glacial acetic acid is added andstirring is then continued at 20 C. for 5 minutes. The reaction mixtureis next poured into 1 liter of ice water and solid which forms iscollected and dissolved in methylene chloride. This solution is washedwith water, dilute sodium bicarbonate solution and water, dried andevaporated to dryness. The resiue is dissolved in 60 ml. ofdimethylformamide and added to a well stirred suspension of 12.5 g. ofcalcium carbonate in 440 ml. of dimethylacetamide, heated at reflux.Refluxing is continued for 45 minutes and the mixture is then filteredand concentrated to about 60 ml. under reduced pressure. After theaddition of 5 ml. of hexane, the mixture is filtered and the filtrate isevaporated to dryness. The residue is chromatographed on acid Washedalumina with 3:1 benzenezchloroform to yield 16a,17ot-ethylene-5a-pregn-1-en-3,20-dione which may be recrystallized fromcyclohexane:ethyl acetate.

A solution of 45 equivalents of sodium chlorodifluoroacetate in 50 ml.of triethylene glycol dimethyl ether is added in a dropwise fashion to arefluxing solution of1606,l70L-8'thYlfi1'l6-50L-pI'Bg1'l-1-6I1-3,ZO-dlOIle in 10 ml. oftriethylene glycol dimethyl ether. Refluxing is discontinued upon theabsence of any change in the UV. spectra and the mixture is thenfiltered and evaporated to dryness under reduced pressure. The residueis then heated at reflux for one hour with a 1% methanolic solution ofpotassium hydroxide. At the end of this time, the reaction mixture isneutralized with dilute hydrochloric acid and evaporated to dryness. Theresidue is then chromatographed on alumina with methylene chloride toyield 1u,2a-diiluoromethylene-16a,17a-ethylene-5a-pregname-3,20-dione.

To a stirred solution of 1 g. of 1u,2ot-difluoromethylene-16a,17rx-ethylene-5a-pregnane-3,20-dione and 6.6 g. of p-toluenesulfonicacid in 330 ml. of glacial acetic acid is added over a 10 minute period,a solution of 1.1 molar equivalents of bromine and 2.45 g. of sodiumacetate in 110 ml. of glacial acetic acid. After stirring for anadditional 10 minute period, a solution of g. of sodium acetate in 150ml. of glacial acetic acid is added and stirring is then continued at 20C. for 5 minutes. The reaction mixture is next poured into 1 liter ofice water and the solid which forms is collected and dissolved inmethylene chloride. This solution is washed with water, dilute sodiumbicarbonate solution and water, dried and evaporated to dryness. Theresidue is dissolved in 60 ml. of dimethylformamide and added to a wellstirred suspension of 12.5 g. of calcium carbonate in 440 ml. ofdimethylacetamide, heated at a reflux. Refluxing is continued for 45minutes and the mixture is then filtered and concentrated to about 60ml. under reduced pressure. After the addition of 5 ml. of hexane, themixture is filtered and the filtrate is evaporated to dryness. Thisresidue is chromatographed on acid washed alumina with 3:1 benzene:chloroform to yieldlot,2a-difluoromethylene-l6ix,17aethylenepregn-4-ene-3,ZO-dione whichmay be recrystallized from cyclohexanezethyl acetate.

Using the same procedure 3fi,l7ot-dihydroxy-l9-norpregnan-ZOone givesthe corresponding 19-nor compound, namely1a,2a-difluoromethylene-16a,17a-ethylenel9-norpregn-4-en-3,20-dione.

EXAMPLE 2 A solution of l g. of l7a-hydroxy-l9-norprogesterone and 0.1g. of p-toluenesulfonyl chloride in 1 ml. of acetic anhydride and 100ml. of benzene is allowed to stand at 20 C. for six hours. The organicphase is washed with water and aqueous 5% sodium bicarbonate solution toneutrality, dried over sodium sulfate and evaporated to yield 3 acetoxy17a hydroxy-l9-norpregna-3,5-dien-20= one which may be crystallized fromacetonezhexane.

To a stirred solution of 1 g. of 3-acetoxy-17u-hydroxy19-norpregna-3,5-dien-20 -one in 30 ml. of ethanol and 1 ml. of Water,under nitrogen is added 0.84 g. of methoxy amine hydrochloride and 1.1g. of potassiumzacetate. The mixture is heated at reflux for 18 hours.The suspension is cooled and diluted with 40 ml. of water. The solid iscollected by filtration, washed With water and dried to yield 3 acetoxyl7a-hydroxy-20-methoxyimino-19-norpregna-3,5-diene.

A solution of 6 g. of 3,8-acetoxy-17a-hydr0xy-20-methoxyimino-l9-norpregna-3,5-diene in 100 ml. of ethanol and 35 ml. oftetrahydrofuran is cooled to 10 C. and added dropwise over a 1 hourperiod to a stirred, cooled solution of 6 g. of sodium borohydride in 50ml. of 80% ethanol, the reaction temperature being maintained below 5 C.Upon completion of addition, the solution is allowed to stand at 0 C. to5 C. for 2 hours. Two hundred milliliters of 10% sodium hydroxidesolution are then added and the solution heated at the boiling point for15 minutes. The solvent is evaporated under reduced pressure and theresidue is acidified with 20% hydrochloric acid. The solid which formsis collected by filtration, washed with water and dried to yield 35,17-dihydroxy 20 methoxyimino-l9-norpregn-5-ene which may be furtherpurified by recrystallization from acetone.

To a solution of 1 g. of35,l7a-dihydroxy-20-methoxyimino-l9-norpregn-5-ene in 10 ml. of pyridineat 40 C. is added quickly 0.4 ml. of thionyl chloride in 10ml. ofpyridine. The mixture is held at -40 C. under a nitrogen atmosphere fora period of 1 hour. The mixture is then poured into ice and water. Thesolid is collected by filtration to give3fl-hydroxy-20-rnethoxyimino-l9-norpregna- 5,16-diene. To a solution ofthis material in ml. of acetone is added 100 nil. of 2 N hydrochloricacid and the mixture is allowed to stand at 25 C. for 72 hours. Theproduct is extracted with chloroform and washed to neutrality with waterand sodium bicarbonate solution. The solvent is removed by evaporationunder reduced pressure, and the 3B-hydroxy compound is treated with 8ml. of acetic anhydride in 10 ml. of pyridine to yieldBB-acetoxy-l9-norpregna-5,16-dien-20-one.

7 EXAMPLE 3 A mixture of 2 g. of 3-acetoxypregna-5,l6-dien-20-one in 140ml. of benzene is irradiated with a 70 watt Hanan high pressure mercuryvapor lamp with a Pyrex filter at room temperature while bubblingethylene through the solution. At the end of reaction time, which may bedetermined by U.V. spectroscopy, the reaction mixture is evaporated invacuo to dryness, chromatographed on silica and the product eluted withethyl acetatezbenzene to yield 3 acetoxy l6a,17aethylenepregn-S-en-20-one which is recrystallized frommethanolzmethylene chloride.

Using the same starting material and the above procedure the followingolefins tetrafluoroethylene, 1,1-difluoroethylene, butene-2, allylchloride, 1-chloro-1,2,2- trifluoroethylene, isobutylene, 1,1dimethoxyethylene, vinyl acetate and styrene, aflorded 3 ,B-acetoxy- 16a, 1 7ix-tetrafluoroethylenepregn- 5 -en--one, 3/3-acetoxy- 16cc, 17all'-difluoro) ethylenepregn- 5 -en-20-one,3B-acetoxy-l6a,17a-(1',2'-dimethyl)ethylenepregn- 5 -en-20-one,3,8-acetoxy-l6a,17a-(1'-chloromethyl)ethylenepregn- S-en-ZO-one,3fl-acetoxy-l6a,l7u-(1-chloro-1,2',2'-trifluoro)ethylenepregn-S-en-ZO-one,3B-acetoxy-l6a,17a-(1',1'-dimethyl)ethylenepregn- 5-en-20 one,3fl-acetoxy-l6u,17a-(1,1'-dimethoxy)ethylenepregn- 5-en-20-one,3fl-acetoxy-16a,17 x-(1-acetoxy)ethylenepregn- 5 -en-20-one,3B-acetoxy-16a,17a-( l-phenyl)ethy1enepregn- 5-en-20-one, respectively.

Allene with the same starting material affords a mixture of the16u,17a(l-methylene), and l6a,l7a(2- methylene) products Which areseparated by column chromatography. The l,l-dilfuoroallene likewiseaflords a mixture of products which are separated by columnchromatography.

EXAMPLE 4 Using the same procedure and olefins described in Example 3, 3acetoxy 19 norpregna 5,16 dien 20- one is allowed to react with thoseolefins to give the following products, namely 3 l9-acetoxy- 1 6a,l7a-ethylenel 9-norpregn- 5 -en-20- one,

3,8-acetoxy-16a,l7a-tetrafluoroethylene-19-norpregn- 5-en-20-one,

3fl-acetoxy-l6a,17a-(2-methylene)ethylene-l9- norpregn-S -en-20-one,

3fi-acetoxy- 1 60,170L- 1',2'-dimethyl ethylene-19-norpregn-S-en-ZO-one,

3 [iacetoxy- 1 6a, 1 7a-( 1-chloromethyl ethylene-19-norpregn-5-en-20-one,

3B-acetoxy-16a,17ix-(2'-difluoromethylene)ethylenel9-norpregn-5-en-20one,

3/i-acetoxy-16a, 17u-( l, l'-dimethyl) ethylene-19-norpregn-S-en-ZO-one,

3I3-acetoxy-16a, 1711- l l'-dimethoxy) ethylene- 19- norpregn-S-en-ZOone, and

3fl acetoxy-16a, l7ocl '-acetoxy) ethylenel9- norpregn-S-en-ZO-one.

EXAMPLE 5 hydride and 50 ml. of acetyl chloride is heated at reflux for4 hours under nitrogen. The reaction mixture is then distilled to almostdryness, cooled and diluted with ether. The organic phase is washed withwater, aqueous 5% sodium bicarbonate solution and again with water,dried over sodium sulfate and evaporated to yield 1zx,2zxdifluoromethylene 3B acetoxy 16oc,17ot ethylenepregna 3,5 dien 20 onewhich may be recrystallized from acetonezhexane.

A solution of 6 g. of 10 20: difluoromethylene 3B- acetoxy 16a,17ocethylenepregna 3,5 dien 20 one in 100 m1. of ethanol and 35 ml. oftetrahydrofuran is cooled to 10 C. and added dropwise over a 1 hourperiod to a stirred, cooled solution of 6 g. of sodium borohydride in 50ml. of 80% ethanol, the reaction temperature being maintained below 5 C.Upon completion of addition, the solution is allowed to stand at 0 C.

for 2 hours. Two hundred milliliters of 10% sodium hydroxide solutionare then added and the solution heated at the boiling point for 15minutes. The solvent is evaporated under reduced pressure and theresidue is acidified with 20% hydrochloric acid. The solid which formsis collected by filtration, washed with water and dried to yield 106,206difluoromethylene 3B hydroxyl6u,17a ethylenepregn 5 en 20 one which maybe further purified by recrystallization from acetone.

A mixture of l g. of la,2 z-difluoromethylene3fl-hydroxy l6ot,17 xethylenepregn 5 en 20 one, 4 ml. of pyridine and 2 ml. of aceticanhydride is allowed to stand at room temperature for 15 hours. Themixture is then poured into ice water and the solid which forms iscollected by filtration, washed with water and dried to yield 1at,2otdifluoromethylene 3/9 acetoxy 16a, 17a ethylenepregn 5 en 20 one whichmay be further purified through recrystallization from acetone: hexane.

Using the same procedure 1a,2a-methylene-16a,l7aethylene l9 norpregn 4ene 3,20 dione is converted to 10,20L methylene 3B acetoxy16oc,17aethylene-l9-norpregn-5-en-20-one.

EXAMPLE 6 A mixture of 2 g. of 3-acetoxy-16a,l7a-ethylenepregn-5-cn-20-one in 30 ml. of 2-methyl-2-ethyl-1,3-dioxolane and 70 mg. ofp-toluenesulfonic acid is heated at reflux with distillation for onehour. The mixture is then cooled diluted with Water and extracted withethyl acetate. The extracts are washed to neutrality, dried andevaporated to dryness to yield3-acetoxy-16a,17a-ethylene-20-ethylenedioxypregn-S-ene which isrecrystallized from acetone: hexane.

A solution of 2.5 g. of 3-acetoxy-16a,17a-ethylene-20-ethyl-enedioxypregn-S-ene in ml. of chloroform is cooled to 0 C. andmixed with a solution of 1.1 molar equivalents of monoperphthalic acidin ether. The mixture is allowed to stand at room temperature for 20hours and then diluted with water. The organic layer is separated,washed with aqueous sodium bicarbonate solution and then with Water toneutrality, dried over sodium sulfate and evaporated to dryness to yield3-acetoxy-5u, 60c oxido 16a,17 x ethylene 20 ethylenedioxypregnane whichmay be further purified by recrystallization from acetonezhexane.

To a stirred solution of 20 ml. of 4 N methylmagnesium bromide in etheris added a solution of 1 g. of 3 acetoxy 50:,60: oxido 16a,17a ethylene20- ethylenedioxypregnane in 30 ml. of dry tetrahydrofuran, and thestirred mixture is heated at reflux temperatures for 30 minutes. Thereflux condenser is then replaced by a calcium chloride drying tube andthe ether is allowed to escape. When the internal temperature is 54 C.,the condenser is returned and the mixture refluxed for an additional4-hour period. Two hundred milliliters of a saturated ammonium chloridesolution are then slowly added to the cooled mixture which is thenstirred for 15 minutes and extracted with ethyl acetate. These extractsare washed with water, dried over sodium sulfate and evaporated todryness to yield 3fl,5a-dihydroxy-6fl-methyl 16a,17u ethylene 20ethylenedioxypregnane which is recrystallized from aqueous methanol.

A mixture of g. of 35,5a-dihydroxy-6fl-methyl-16a, 17a ethylene 20ethylenedioxypregnane, 400 ml. of acetic anhydride and 1 drop ofconcentrated sulfuric acid is stirred at room temperature for hours. Theresulting solution is poured into water and extracted with methylenechloride. The extracts are washed with 10% aqueous sodium bicarbonatesolution and then with Water to neutrality, dried over sodium sulfateand evaporated to dryness. The residue is chromatographed on neutralalumina to yield 3,6 hydroxy 6 methyl16a,17uethylene--ethylenedioxypregn-S-ene which further purified throughrecrystallization from acetone2hexane.

A mixture of 0.5 g. of 3B-hydroxy-6-methyl-16a,17aethylene-ZO-ethylenedioxypregn-S-ene in ml. of acetone and 50 mg.of p-toluenesulfonic acid is allowed to stand at room temperature for 15hours. It is then poured into ice water and extracted with ethylacetate. These extracts are washed with water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is triturated withether to yield 3Bhydroxy-6-methyl-16a, 17a-ethylenepregn-5-en-20-onewhich is recrystallized from acetonezhexane.

EXAMPLE 7 One gram of 3,8acetoxy-16a,l7a-ethylenepregn-5-en- ZO-one isallowed to stand at room temperature for 15 hours with 1 g. of potassiumbicarbonate in 10 ml. of water and 90 ml. of methanol. At the end ofthis time, the methanol is evaporated under reduced pressure and theresidue is extracted with ethyl acetate and water. Evaporation of theethyl acetate from these extracts yieldshydroxy-l6a,17a-ethylenepregn-5-en-20-one which is collected byfiltration and recrystallized from acetone: hexane.

A solution of l g. of SIS-hydroxy-16ot,17a-ethylenepregn- 5-en-20one in80 ml. of toluene and 20 ml. of oyclohexanone is dried by removing 10ml. of solvent by distillation. A solution of 1 g. of aluminumisopropoxide in 7 ml. of anhydrous toluene is then added and the mixturerefluxed for minutes. Four milliliters of acetic acid are added and thesolvents removed by steam distillation. The residue is extracted severaltimes with ethyl acetate and these extracts are then washed with 5%hydrochloric acid solution, water, 10% sodium carbonate solution andwater to neutrality, dried over anhydrous sodium sulfate and evaporatedto dryness to yield 16a,17a-ethylenepregn- 4-ene-3,20-dione which may befurther purified by recrystallization from acetonezhexane.

To a suspension of 1 g. of l6a,17ot-ethylenepregn-4- ene-3,'20-dione in7.5 ml. of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. Themixture is stirred at room temperature for 15 minutes and allowed tostand at room temperature for 30 minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield 3-ethoxy-16a,17ot-ethylenepregna-3,S-dien-20-one which is recrystallizedfrom aoetone:hexane.

Using the same procedure those final products in Examples 3 and 4 areconverted to their respective analogs, namely the 3-ethoxy-A -compounds.

EXAMPLE 8 A solution of 1 g. of 3-ethoxy-16a,l7a-ethylenepregna-3,5-dien-20-one in iodotrifluoromethane containing pyridine isirradiated at room temperature with ultraviolet light from a highpressure mercury lamp. At the end of the reaction time which may bedetermined by U.V. spectroscopy, the reaction mixture is evaporated todryness to yield 3-ethoxy-6-trifluoromethyl-16a,17ot-ethylenepregna-3,5-dien-20-one which is recrystallized frompentane.

To a solution of 1 g. of 3-ethox'y-6-trifluoromethyl-16a,17a-ethylenepregna-3,5-dien-20-one in 10 ml. of acetone are added a fewdrops of 36% hydrochloric acid. The mixture is heated a few minutes atsteam bath temperatures, diluted with water and filtered. The solid thuscol lected is dried and recrystallized from acetone:hexane to yield6ot-trifluoromethyl-l6a,17a ethylenepregn-4-ene- 3,20 dione.

Using the same procedure 3-ethoxy-16a,l7wtetraflu0r0-ethylene-19-norpregna-3,5-dien 2O one yields 60c trifiuoromethyl 16a,17atetrafluoroethylene-1'9 norpregn- 4-ene-3,2 0-dione.

EXAMPLE 9 A mixture of 5 g. of 3-ethoxy-1 6a,l7a-ethylenepregna-3,5-dien-20-one, 2 g. of anhydrous sodium acetate and ml. of acetone istreated with 32 ml. of water. The solution is cooled to 5 C. and 1.1molar equivalents of N-chlorosuccinimide and 2 ml. of glacial aceticacid are added. The mixture is stirred for 30 minutes at the sametemperature and then diluted with Water. After being allowed to stand at0 C. for 15 hours, the solid is collected by filtration, washed withwater and dried under vacuum to yield -6fi-chloro-16x,17a-ethylenepregn-4-ene-3,20-dione which is recrystallized fromacetone. The corresponding 6OL-ChlOI'O compound is obtained bydissolving this compound in glacial acetic acid and introducing a slowstream of anhydrous hydrogen chloride over a period of four hours and atemperature of 15 C. The solid which forms upon pouring this mixtureinto water is collected by filtration, washed with water and dried toyield 6u-chloro-16a, l7a-ethylenepregn-4-ene-3,20-dione which isrecrystallized from acetonezhexane.

Using the same procedure 3-ethoxy-1 6a,Hot-ethylene-19-norpregna-3,5-

dien-ZO-one,

3 -ethoxy- 1 6a, 17 u-tetrafiuoroethylene-pregna- 3,5-dien-20-one,

and 3-ethoxy-16a,l7ot-tetrafluoroethylene- 19-norpregna-3,5-dien-20-one,

and 1a,2a-difluoromethylene3-ethoxy-16a,17a-ethylenepregna-3,S-diene-ZO-one and1a,2ot-difluoromethylene-3-ethoxy-16a,17a-

1,1-difluoro)ethylenepregna-3,5-diene-20-one are converted to6a-chloro-16ot,17at-ethy1ene-19 n0rpregn-4-ene-3,20-dione,6a-chloro-l6a,17ot-tetrafluoroethylene-pregn- 4-ene-3,20-dione and6a-chloro-1 6a,17a-tetrafluoroethylene-19- norpregn-4-ene-3,20dione,

and 1a,lot-difluoromethylene-Ga-chloro-1 6a,17a-

1, 1'-difluoro -ethylenepregn-4-ene-3,20 dione respectively.

EXAMPLE 10 A stream of perchloryl fluoride is passed through a solutionof 1 g. of 3 ethoxy 16et,17a-(1,1'dimethoxy)ethylenepregna-3,5-dien-20-one in 25 ml. of dimethylformamide, cooled to0 C., for 5 minutes. After being allowed to slowly attain a temperatureof 20 C., the solution is poured into water and extracted with ethylacetate. These extracts are washed with saturated aqueous sodiumbicarbonate solution and with water to neutrality, dried over sodiumsulfate and evaporated to dryness. The residue is then chromatographedon alumina to separate the 6a-fiuoro and 6B-fluoro isomers. The latter,which predominates, is dissolved in 50 ml. of glacial acetic acid andthrough this solution is passed a stream of dry hydrogen chloride for aperiod of 24 hours and at a temperature of 15 C. The mixture is pouredinto cold water To a suspension of 1 g. of 6ot-chloro-16ot,Hut-ethylenepregn-4-en-3,20-dione in 7.5 ml. of anhydrous, peroxidefree dioxane areadded 1.2 ml. of freshly distilled ethyl t orthoformate and 0.8 g. ofp-toluenesulfonic acid. The mixture is stirred at room temperature for15 minutes and allowed to stand at room temperature for 30 minutes.There is then added 0.8 ml. of pyridine, followed by water untilsolidification occurs. This solid is collected by filtration, washedwith water and air dried to yield 3ethoXy-6-chloro-l6a,l7u-ethylenepregna-3,5-diene-20- one which isrecrystallized from acetonezhexane.

To a solution of 1 g. of3-6ih0XY-6-Chl0lO-l60:,l7otethylene-pregna-3,5-dien-20-one in 20 ml. oftetrahydrofuran, cooled to C., is added 1.05 molar equivalents of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 100 mg. ofp-toluenesulfonic acid. The resulting mixture is stirred at 0 C. for 30minutes, filtered, and diluted with 100 ml. of methylene chloride. Theorganic phase is separated, washed with 5% aqueous sodium hydroxidesolution until the washings are colorless and then with water toneutrality, dried over sodium sulfate and evaporated to dryness to yield6-chloro-l6a,17a-ethylenepregna-4,6- diene-3,20-dione which may befurther purified through recrystallization from acetonethexane.

Using the same procedure other A -diene compounds of the presentinvention are prepared. Notably among these are the following:

6-chloro-16a,17a-ethylene-19-norpregna-4,6-diene-3,20-

dione, 6-chloro-16a,17a-tetrafluoroethylenepregna-4,6-diene-3,

-dione, 6-chloro-16a,l7a-tetrafluoroethylene-l9-norpregna-4,6-

diene-3 ,20-dione,6-fluoro-16a,17ot-tetrafluoroethylenepregna-4,6-diene- 3,20-dione,6-fllIOl'O-16a,17a-( 1',2'-dimethyl) ethylene-19-norpregna- 4,6-diene-3,20-dione, 6-fluoro-16a,17u-(1,1-difluoro)ethylenepregna-4,6-

diene-3,20-dione, 6-fluoro-16a,17a-ethylenepregnai,6-diene-3,20-dione,6-methyl-16a,17a-ethylenepregna-4,6-diene-3,20-dione,6-trifluoromethyl-16a,17ot-ethylene-19-norpregna-4,6-

diene-3 ,ZO-dione, 1 u,2a-difluoromethylene-6-chloro-16a,Una-ethylenepregna-4,6-diene-3,20-dione, la,2a-mthYlCI16-6Chl010-16a,17a-ethylenepregna-4,6-

diene-3,20-dione, and 1a,2o-methylene-6-chloro-l6a,17a-(l,1',-difluoro)ethylenepregna-4,6-diene-3 ,20-dione.

EXAMPLE 12 A mixture of 0.5 g. of 6cc-ChlO10-l60:,l7ot-6thYl6I16-pregn-4-ene-3,20-dione, 10 ml. of dioxane and 0.35 g. of

2,3-dichloro-5,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. Themixture is then cooled, filtered and evaporated to dryness, The residueis dissolved in acetone and this solution is then filtered through 10 g.of alumina and concentrated to yield6a-chloro-16a,17aethylenepregna-1,4-diene-3,20-dione which is furtherpurified by recrystallization from acetoneshexane.

Using the same procedure other A compounds are prepared. Notably amongthese are the following:

60t-Cl1lOfO-16ot, 17a-tetrafluoroethylenepregna-1,4-diene- 3,20-dione,

ficc-flUOI'O- 1 60a, l7a-tetraflu oroethylenepregn a- 1 ,4-diene-3,20-dione,

6a-trifluoromethyl-l6a,l7ot-ethylenepregna-1,4-diene- 3,20-dione,respectively.

EXAMPLE 13 To a solution of 1 g. of3-acetoxy-16u,Not-ethylenepregn-5-en-20-one in 20 ml. oftetrahydrofuran, cooled to 0 C., is added 1.05 molar equivalents of2,3-dichloro- 5,6 dicyano 1,4 benzoquin one and mg. of p-toluenesulfonicacid. The resulting mixture is stirred at 0 C. for 30 minutes, filtered,and diluted with 100 ml. of methylene chloride. The organic phase isseparated, washed with 5% aqueous sodium hydroxide solution until thewashings are colorless and then with water to neutrality, dried oversodium sulfate and evaporated to dryness to yield16a,17a-ethylenepregna-4,6-diene-3,20-dione which may be furtherpurified through recrystallization from acetonezhexane.

To a stirred and refluxing solution of 1 g. of16a,17aethylenepregna-4,6-diene-3,ZO-dione in 8 ml. of dimethyldiethyleneglycol ether is added in a dropwise fashion over a two-hourperiod, a solution of 30 equivalents of sodium chlorodifluoroacetate in30 ml. of dimethyl diethyleneglycol ether. At the end of the reactionperiod, which may be followed by the U.V. spectra, the mixture isfiltered and evaporated in vacuo to dryness. The residue is added to 10%methanolic potassium hydroxide and this mixture is heated briefly atreflux and poured into ice water. The solid which forms is collected,washed with water, dried and chromatographed on alumina, eluting withmethylene chloride, to yield 6u,7u-difluoromethylene-16a,17a-ethylenepregn-4-ene-3,20-dione.

Using the same procedure the following compounds, namely3-Z1C6t0Xy-l6oc,l7oc-( l, l -dimethyl) ethylenepregn-S-en- 20-one,3-acet0xy-16a,17wethylene-l9-norpregn-5-en-20-one,3-acetoxy-l6a,17a-tetrafluoroethylenepregn-5-en-20-one,

and 3-acetoxy-16a,17a-(1,1-dimethoxy)ethylenepregn-S-en- 20-one areconverted to6a,7ot-difluoromethylene-16u,17a-(1,2-dimethyl)ethylenepregn-4-ene-3,20-dione,6oL,7oc-difll1OIOmCthy16n16a, Not-ethylene-19-norpregn- 4-ene-3,20-dione,6u,7a-difluoromethylene-16a,17ot-tetrafluoroethylenepregn-4-ene-3,20-dioneand 6a,7a-difluoromethylene-16a,17a-(1,1'-dimethoxy)-ethylenepregn-4-ene-3 ,20-dione, res pectively.

EXAMPLE 14 A solution of 1 g. of sodium borohydride in 3 ml. of water isadded to an ice-cooled solution of 1 g. of160:,17aethylenepregna-4,6-diene-3,20-dione in ml. of methanol and themixture then allowed to stand for 16 hours at room temperature. Theexcess reagent is decomposed by addition of acetic acid and the solutionis then concentrated to small volume in vacuo and diluted with water.The product is extracted with ethyl acetate and these extracts arewashed with water, dried and evaporated to yield16a,17a-ethylenepregna-4,6-diene-3,20-diol which may be further purifiedby recrystallization from acetone: hexane.

A solution of 0.5 g. of 16a,17a-ethylenepregna-4,6- diene-3,20-diol inml. of dimethylsulfoxide is added to a solution of one equivalent ofdimethylsulfoxonium methylide in dimethylsulfoxide, prepared in themanner of Corey et al., J. Am. Chem. Soc., 87, 1353 (1965). The mixtureis stirred under nitrogen at room temperature for 20 hours and then at50 C. for 7 hours. Fifty milliliters of water are then added and theresulting mixture extracted four times with 50 ml. of ethyl acetate. Thecombined extracts are washed with water and saturated aqueous sodiumchloride solution, dried over sodium sulfate and evaporated to dryness.This residue is then chromatographed on silica, eluting withetherzmethylene chloride to yield6u,7a-methylene-16a,17a-ethylenepregn-4- ene-3,20-diol.

One gram of 6u,7u-methylene-16a,17a-ethylenepregn- 4ene-3,20-diol in 100ml. of chloroform is stirred for 18 hours at room temperature with g. offreshly precipitated manganese dioxide. The inorganic material is thenremoved by filtration and washed with hot chloroform and the combinedfiltrate and washings are evaporated to yield 60,7otmethylene-16a,17u-ethylene-20-hydroxypregn-4-en-3-one. This material in120 ml. of pyridine is then added to a mixture of 6 g. of chromictrioxide in ml. of pyridine. The mixture is allowed to stand at roomtemperature for 15 hours. The inorganic material is removed byfiltration and the filtrate evaporated to dryness to yield 6u,7a-methylene-l6u,17wethylenepregn-4-ene-3,20 dione.

Using the same procedure, other A -diene intermediates are converted totheir corresponding 6u,7u-methylene analogs. Notably among these are thefollowing:

6a,7ix-methylene-16a,17a-(1,2'-dimethyl)ethylenepregn-4-ene-3,20-dione,

6u,7u-methylene-16a,17a-ethylene-19-norpregn-4-ene- 3 ,20-dione,

6a,7u-methylene-l6u,17u-tetrafiuoroethylenepregn-4- ene-3 ,20-dione and6a,7a-methylene--16a,17a-( 1,1'-dimethoxyethylenepregn-4-ene-3,20-dione.

Using the same procedure, A -ene compounds are converted to thecorresponding lulu-methylene compounds. Notably among these are thefollowing: lulu-methylene- 16a,17a-ethylene-5a-pregnane-3,20dione andlulu-methylene-l6a,17a-ethylene-5a-19-norpregnane-3,20-dione.

EXAMPLE 15 A mixture of 1 g. of 6-chloro-16a,17a-ethylenepregna-4,6-diene-3,20-dione, 2 g. of chloranil and 10 ml. of namyl alcohol arerefluxed under nitrogen for 24 hours. The mixture is then cooled, washedwith a cold aqueous solution of 10% sodium hydroxide until the washingsare colorless, dried over sodium sulfate and evaporated. Chromatographyof the residue on neutral alumina yields 6-chloro-l6u,17a-ethylenepregna 1,4,6 triene-.3,20-dione which may befurther purified through recrystallization from acetonezhexane.

Using the same procedure the final products of Example 11 are convertedto their respective A -triene analogs, respectively.

EXAMPLE 16 A solution of 1 g. of out-chloro-16a,17a-ethylenepregn-4-ene-3,20-dione in 50 ml. of tetrahydrofuran is added over a -minuteperiod to a stirred suspension of 1 .g. of lithium aluminum hydride inml. of anhydrous tetrahydrofuran, and this mixture is heated at refluxfor 2 hours. To the mixture are cautiously added 5 ml. of ethyl acetateand 2 ml. of water. Sodium sulfate is next added, the mixture isfiltered and the solid thus collected is washed with hot ethyl acetate.The combined organic solutions are then evaporated to yield3fl-hydroxy-6achloro-160,17a-ethylenepregn-4-en-20-one which may befurther purified through recrystallization from acetone: hexane.

Two milliliters of dihydropyran are added to a solution of 1 g. of3,8hydroxy-6wchloro-16a,17u-ethylenepregn- 4-en20-one in 15 ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution.This mixture is allowed to stand at room temperature for four days, andis then washed with aqueous sodium carbonate solution and water, driedand evaporated. The residue is chromatographed on neutral alumina,eluting with hexane, to yield3B-tetrahydropyranyloxy-6a-chloro-16u,17u-ethylenepregn-4-en-2'0-onewhich is recrystallized from pentane.

Using the same procedure, the following 3-tetrahydropyranyloxy compoundsof the present invention are prepared. Notably a-mong these are thefollowing:

3-tetrahydropyranyloxy-6a-chloro-16a,l7u-tetrafiuoroethylenepregn-4-en-20-one,

3-tetrahydropyranyloxy-16u,17m-ethylene-19-norpregn- 4-en-20-one and3-tetrahydropyranyloxy-6a-chloro-l 6a,17a-tetrafiuoroethylene-19-norpregn-4-en-20-one,

1a,2u-difluoromethylene-3-tetrahydropyranyloxy-6-chloro-16a,17a-ethylenepregna-4,6-dien-20-one.

EXAMPLE 17 A solution of 1 g. of1u,2a-difiu0romethylene-1604,17ozethylenepregn-4-ene3,20-dione in 50 ml.of tetrahydro furan is added over a 30-minute period to a stirredsuspension of 1 g. of lithium aluminum hydride in 50 ml. of anhydroustetrahydrofuran, and this mixture is heated at reflux for 2 hours. Tothe mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. ofwater. Sodium sulfate is next added, the mixture is filtered and thesolid thus collected is washed with hot ethyl acetate. The combinedorganic solutions are then evaporated to yield1oc,20z-difluorornethylene-3fi-hydroxy 1611,17 ethylenepregn-4-en-20-one which may be further purified through recrystallization fromacetone:hexane.

A mixture of 1 g. of 1a,2ot-difluoromethylene-3[a-hydroxy-l6a,17a-ethylenepregn-4-en-20-one, 4 ml. of pyridine and 2mlfi'of acetic anhydride is allowed to stand at room temperature for 15hours. The mixture is then poured into ice water and the solid whichforms is collected by filtration, washed with water and dried to yield1m,2a-difluoromethylene-3,8-acetoxy 16,l7a ethylenepregn-4-en-20-onewhich may be further purified through recrystallization fromacetonezhexane.

Using the same procedure and starting material but utilizing propionicanhydride and then cyclopentylpropionic anhydride in place of aceticanhydride the corresponding 3,8-propionate and 3fi-cyclopentylpropionateare obtained, respectively.

EXAMPLE 18 To a stirred solution of 1 g. ofGot-ChlOIO-l6a,17aethylenepregn-4-ene-3,ZO-dione in 40 ml. of dioxane isadded in a dropwise fashion a solution containing 1.2 molar equivalentsof bromine in dioxaneat a temperature of 15 C. The mixture is allowed tostand at room: temperature for 30 minutes and then poured into 5%aqueous sodium bicarbonate solution and extracted with chloroform. Theseextracts are washed with water, dried over sodium sulfate and evaporatedunder reduced pressure, to yield6a-chloro-16u,17methylene-21-bromopregn-4-ene- 3,20-dione which isfurther purified through recrystallization from methylenechloridezhexane.

To a stirred solution of the bromo intermediate in 40 ml. ofdimethylforvmamide is added a 1.1 molar equivalent of lithium chloride.The reaction mixture is held at C. for a period of 2 hours, poured intoice water, and extracted with chloroform. The organic phase is washedwith water, dried and evaporated to dryness to yield 60:-

chloro-16a,17a-ethylene-2l-chloropregn 4 ene 3,20 dione.

Using the same procedure the starting compounds namely6ot-chloro-16a,17ot-tetrafluoroethylene 19 norpregn-4-ene-3,20-dione,60ctrifluoromethyl-l6a,17a-tetrafluoroethylene-19-n01pregn-4-ene-3,ZO-dioneand 60a fluoro-loa,17a-ethylenepregn-4-en-3,20-dione are converted tothe corresponding 21-chloro compounds.

EXAMPLE 19 The Got-chloro-16a,17u-ethylene-2l-bromopregn-4-ene-3,20-dione is dissolved in ml. of acetonitrile and treated dropwise with1.4 g. of silver fluoride in 3 ml. of water. The mixture is allowed tostand at room temperature for 24 hours and then filtered. The filtrateis concentrated under vacuum and the solid which forms is collected anddried to yield 6a-chloro-16a,l7a-ethylene2l-fluoropregn-4-ene-3,20-dione which is recrystallized frommethanolzacetone.

Using the same procedure those 21-bromo compounds of Example 18 areconverted to their 2l-fluoro analogs, respectively.

What is claimed is:

1. A compound of the formula CHzR wherein Z is a carbon-carbon singlebond, a carbon-carbon double bond or the group bridging the C-1 and C-2carbon atoms, each of X and Y being hydrogen, chloro or fluoro;

Z is a carbon-carbon single bond, a carbon-carbon double bond or thegroup bridging the C-6 and C-7 carbon atoms, each of X' and Y beinghydrogen, chloro or fluoro;

R is hydrogen, chloro or fiuoro;

R is hydrogen, fluoro, chloro, methyl or trifiuoromethyl;

R is hydrogen or methyl; R being methyl when Z is a carbon-carbon doublebond;

R is an oxygen atom or the group,

in which R is hydrogen, tetrahydropyranyl or a hydrocarbon carboxylicacyl group of less than 12 carbon atoms;

each of A and B is hydrogen, chloro, fluoro or an alkyl group of from 1to 4 carbon atoms;

each of D and E is hydrogen, chloro, fluoro, phenyl, an alkyl group offrom 1 to 4 carbon atoms, an alkoxy group of from 1 to 4 carbon atoms ora haloalkyl group of from 1 to 4 carbon atoms; and

A and B or D and E taken together are methylene or difluoromethylene,provided that Z is a carbon-carbon single bond or a carbon-carbon doublebond whenever Z is the group 15 2. Compounds of claim 1 wherein R ishydrogen; R is hydrogen or chloro; R is oxygen or the group H 11 0-; inwhich R is hydrogen, tetrahydropyranyl or acetyl;

, Z is a carbon-carbon single bond;

Z is a carbon-carbon single bond or a carbon-carbon double bond;

each of A, B, D and E is hydrogen or fluoro and R is as therein defined.

3. Compound of claim 2 wherein R is hydrogen;

R is methyl;

R is oxygen;

Z is a carbon-carbon single bond; and

each of A, B, D and E is hydrogen.

4. Compound of claim 2 wherein R is chloro;

R is methyl;

Z is a carbon-carbon double bond; and

each of A, B, D and E is hydrogen.

5. Compound of claim 2 wherein R is hydrogen;

R is methyl;

R is oxygen;

Z is a carbon-carbon single bond;

each of A, B, D and E is fluoro.

6. Compound of claim 2 wherein each of R and R is hydrogen;

R is oxygen;

Z is a carbon-carbon double bond; and

each of A, B, D and E is hydrogen.

7. Compounds of claim 2 wherein R is chloro;

R is hydrogen;

Z is a carbon-carbon double bond; and

each of A, B, D and E is hydrogen.

8. Compound of claim 1 wherein R is hydrogen;

R is chloro;

R is methyl;

R is oxygen;

Z is the group "oXY bridging the C-1 and C2 carbon atoms, each of X andY being hydrogen;

Z is a carbon-carbon double bond; and

each of A, B, D and E is hydrogen.

9. Compound of claim 1 wherein R is hydrogen;

R is chloro;

R is methyl;

R is oxygen;

Z is the group 11. Compound of claim 1 wherein R is methyl;

each of R and R is hydrogen; R is oxygen;

R is methyl; each of Z and Z is a carbon-carbon single bond;

R is oxygen; each of A, B, D and E is hydrogen.

Z is a carbon-carbon single bond; 16. A compound selected from the groupconsisting of Z is the group CH3 bridging the C-6 and C-7 carbon atoms,each of X 10 p CH2 0 and Y being fiuoro; and R3 each of A, B, D and E ishydrogen. a 12. Compound of claim 1 wherein L/ R is hydrogen; R ischloro; R is methyl; R is oxygen; CH3 Z is the group =0 HGXY I bridgingthe C1 and C-2 carbon atoms, each of X l I 0 0 CH3 and Y being fluoro; HZ is a carbon-carbon double bond; and 0: each of A, B, D and E ishydrogen. 13. Compound of claim 1 wherein 3 R is hydrogen; R is fiuoro;R is methyl; 0:0 R is oxygen; 0112 Z is a carbon-carbon single bond; N Zis a carbon-carbon double bond; and R3 -------COCCH3 each of A, B, D andE is hydrogen. 14. Compound of claim 1 wherein each of R and R ishydrogen; CH3' GH2 0 R is oxygen; 9 wherein R is hydrogen or acetyl andR is hydrogen or Z is a carbon-carbon double bond; methyl.

Z is the group References Cited UNITED STATES PATENTS 3,338,928 8/1967Beard et a1.

bridging the C-6 and C-7 carbon atoms, each of X Y being fiuoro; andENCH p E each of A, B, D and E is hydrogen. HENRY A FR Hmary xammer 15.Compound of claim 1 wherein US, Cl, X R

1 E2 fijfg j 260-43955, 397.4, 397.47, 397.5, 999

